Artificial nipple for experimental animals

ABSTRACT

It is intended to provide an artificial nipple, whereby a liquid feed or a test solution can be voluntarily and orally given to experimental animals with a need for feeding such as mouse infants, a feeding bottle appropriately usable in combination with the nipple, a device for feeding a liquid comprising them, and a method of feeding a liquid. The artificial nipple is characterized by having a replaceable duct therein and having a structure preventing a liquid from piling up in the nipple except in the nipple tip and the duct, while the feeding bottle is characterized by having a replaceable tube therein.

TECHNICAL FIELD

The present invention relates to an artificial nipple favorably used forgiving a liquid feed or a test solution such as a drug solution toexperimental animals voluntarily and orally, a feeding bottle designedto be favorably used in combination with the nipple, a liquid feedingdevice for experimental animals comprising the artificial nipple and thefeeding bottle, and a method for using the same.

BACKGROUND ART

In development researches of pharmaceuticals, nutritional foods, andspecified functional foods, and in a variety of basic researches,acquisition of data from experimental animals is essential work.Especially, mouse or rat infants correspond to human immature babieswhose eyes and ears have not been opened, and have high sensitivity todrugs and the like because of their immature organs. Therefore, data ofhigh accuracy is expected to be obtained from these animals.

When these experimental animals with a need for suckling such as infantsare fed with e.g., milk, a compulsory feeding method is dominantlyemployed in which a feed is given to a gastrointestinal tract using agastric probe or a catheter. This method must be employed because ingiving milk or a test solution, it is necessary to control the doseamount or the dose interval depending on the purpose of the study.However, according to the above method, invasion to organisms, forexample, abraded wounds on the pharynx or esophagus in the case of agastric probe, and wounds created in attaching a catheter is inevitable.As a result, inflammations caused by damages to viscous walls result indata variation among individuals of experimental animals at higherpossibility. In the situation that an experimental animal must take milkor a test solution voluntarily due to the purpose of the study, forexample, for developing milk having a specific application, the methodusing a gastric probe or a catheter which is a compulsory administrationmethod cannot be employed. Apart from the study purpose, use of agastric probe or a catheter with respect to a mouse or rat infant havinga body weight of less than 3 grams will inflict damages on a very softpharynx, esophagus, or gastric wall by a probe needle or the like atvery high possibility.

While accurate data is expected to be obtained by using mouse or ratinfants for development of pharmaceuticals or specified purpose milksuch as milk for immature baby, practically, there is no method forquantitatively feeding mouse or rat infants with milk or a test solutionvoluntarily and orally at a single dose or repeatedly in safety.

In the course of developing an administration method of liquid feed orthe like to experimental animals, the inventors of the presentapplication have developed an automated artificial feeding device forexperimental animals that enables experimental animals to voluntarilydrink milk via an artificial nipple or the like without using a gastricprobe or the like. This is reported in CONTEMPORARY TOPICS in LaboratoryAnimal Science Vol. 35-5, p83-86 (1996).

The feature of the automated artificial feeding device lies in astructure of the artificial nipple. The artificial nipple has a doublestructure so as to prevent milk from leaking when an infant is notdrinking the milk. An outer part of the nipple is formed with a crosscutting at its tip end, and an inner part of the nipple is formed withslits at four positions on its lateral side. Also an injection needlehaving a gauge of 24 to 26G excluding a needle point is inserted intothe nipple. The inventors attempted to prevent milk from leaking and tocontrol the flow by combination of these structural features.

Likewise the present invention, this automated artificial feeding deviceis also designed for an experimental animal to voluntarily stick to theartificial nipple and orally take a liquid feed or the like. However,this device still has the following problems.

1) The previous device is principally designed for rat infants, so thatwhen it is used for mouse infants, it cannot follow the growth of theinfant.

2) The above device fails to feed a test solution or the like in such asimple manner as giving milk to an infant while holding the device withhand as is necessary. Although the above device enabled voluntaryfeeding according to the own will of the rat infant, it is stilldifficult to give a test solution or the like regularly andquantitatively in a specifically controlled manner in practice of theexperiment, for example, to give a test solution according to need.

3) Since the structure of the nipple of this device is too complicatedas an artificial nipple for small animals such as mouse and rat,performance variation between nipples is easy to occur, and it isdifficult to stabilize a feeding amount or the like.

The complicated structure of the previous artificial nipple was devisedfor preventing a liquid feed or the like from leaking from the nipple asdescribed above. However, in order to stabilize the feeding amount andto further improve the reliability of the data, it is desired to developa nipple which is simple in structure in order to replicate the nippleswith ease and excellent in performance, a liquid feeding method forexperimental animals that is designed to be suited to the nipple, and adevice for implementing the same.

DISCLOSURE OF THE INVENTION

In consideration of the above, the inventors of the present applicationattempted to develop a liquid feeding device for experimental animalsand a method of using the same, capable of feeding a liquid feed or atest solution regularly and quantitatively to experimental animals in asimilar manner to breast feeding, by creating an artificial nipplecapable of feeding a liquid feed or a test solution voluntarily andorally in a well-controlled manner even for the cases of very smallexperimental animals whose eyes and ears are still close, such as mouseinfants, and a feeding bottle suited for use in combination with theartificial nipple. The technical problems to be solved by the artificialnipple, the liquid feeding device, and the liquid feeding method aresummarized in the points A to D below.

A. Control of Outflow Degree of Liquid Feed or the Like.

The present invention targets various sizes of experimental animals fromvery small individuals such as mouse infants to individuals as large asferrets, rabbits, and the like. For this reason, it is necessary tocontrol the outflow degree of the liquid feed or the like accurately inaccordance with the size and the condition of the experimental animal.If an excess amount of the liquid feed or the like goes out, it willenter a lung to cause a pneumonia, whereas if the outflow degree is notsufficient, the animal will rapidly stop drinking. When it is necessaryto change the ingredients of the liquid feed or the like depending onthe purpose of the study, the viscosity or the like of the feed or thelike may be changed. In such a case, it is necessary to follow thechange in fluidity of the feed or the like.

B. Prevention of Air Accumulation in a Stomach and Intestines.

When rodents such as mice and rats that are most commonly used asexperimental animals are used as objects of the experiment, since miceand rats cannot produce a belch as a human being does because of itsanatomical positional relationship of stomach, if a mouse or rat takesair at the time of suction-drinking the liquid feed or the like, the airaccumulates in the stomach and intestines, to lead the death in mostcases. Furthermore, since cutting teeth of rodents will growpermanently, when cutting teeth extend to some extent (about 10 daysold), a space is easily created between the nipple and lips due to theextended cutting teeth as an obstacle, resulting that the animal easilysuck air at the time of feeding or administration of a test solution.Therefore, an artificial nipple overcoming this problem is demanded.

C. Comprehension of Feeding Amount of Liquid Feed or the Like.

For research, it is necessary to comprehend the feeding amount of theliquid feed or the like accurately. It should be comprehended forindividual experimental animal, and the comprehension should be realizedsimply during a feeding operation.

D. Artificial Nipple Should Have More Simplified Structure.

The structure of the artificial nipple should be simple but provideexcellent performance in order to facilitate application to a very smallnipple and reduce the variation in feature between individual nipples assmall as possible from the view point of data comparison.

Regarding the point A, first, an artificial nipple has a duct which isreplaceably inserted therein, and by replacing the duct with a duct ofdifferent bore diameter depending on the required flow rate. This makesthe flow rate of the liquid feed or the like controllable. When it isnecessary to control the flow rate more finely, a tube with calibrationsis attached to the feeding bottle, thereby enabling fine adjustment ofthe flow rate by the height (drop difference) of the liquid feed or thelike charged therein.

Secondly, by filling the nipple with silicone rubber, isoprene rubber,styrene-isoprene rubber, or a sponge-like elastic member derivedtherefrom, or forming integrally with the outer wall of the nipple, astructure that prevents the liquid feed or the like from accumulating inthe nipple except in the nipple tip and the duct is realized. In thiscase, when it is formed integrally with the outer wall of the nipple,the nipple may not be filled with an elastic member and the interior maybe hollow. These structures prevent the nipple from being crushed whenan infant bites and sucks the nipple, and prevents the liquid feed orthe like from rushing out at once. This eliminates the necessity ofconstructing the nipple into a double structure, and simplifies thestructure of the nipple. The simplification of the structure can alsoovercome the problem D.

In order to achieve the prevention of liquid leaking and control of theflow rate more securely, the inventors prepared a mechanism thatcontrols the liquid discharge rate by controlling the internal pressureof the closed system interior of the feeding bottle used in combinationwith the artificial nipple. Concretely, a liquid volume adjusting tubehaving a capacity smaller by 20-30% than an expected amount of liquidwhich an infant will drink at one time was attached to the feedingbottle. This liquid volume adjusting tube is designed to be crushed withalmost no resistance in response to the suction-drinking action of theinfant, and will not influence on the suction-drinking action of theinfant. When the liquid volume adjusting tube is crushed, feeding of theliquid will be stopped. In this state, the liquid volume adjusting tubecan be swollen by applying a pressure with hands, fingers, or the likeon a pressurizing tube provided outside the feeding bottle. The infantis allowed to drink a liquid of the volume corresponding to the swollenvolume.

After the infant stops drinking, if the pressurizing with hands orfingers is stopped, the internal pressure of the feeding bottle becomesnegative, the liquid volume adjusting tube is crushed again, and theliquid is prevented from flowing out. As a result, it is possible tofeed a liquid corresponding to the suction-drinking amount by anindividual infant, while preventing a liquid from leaking.

Also it is possible to urge an infant to start suction-drinking with theuse of a pressurizing tube. An infant starts suction-drinking inresponse to inflow of milk or the like rather than entry of a nippleinto the mouth of the infant. Therefore, by applying a slight pressureon the pressurizing tube to cause a small amount of milk to flow out ofthe nipple, it is possible to reduce the time until the infant startssuction-drinking.

With the constitution as described above, the liquid feed or the like isdirectly given from the artificial nipple into the mouth of theexperimental animal from the feeding bottle via the duct in thecondition that the flow rate is controlled. The flow rate of the liquidfeed or the like is first controlled by an inner diameter of the duct.Addition of the structure which prevents accumulation of liquid in thenipple suppresses undesired leaking of the liquid accompanying thesuction-drinking action of the experimental animal. Then, by adding themechanism that makes the internal pressure of the feeding bottle whichis a closed system negative in response to the suction-drinking, thefeeding amount of the liquid is controlled more finely and the liquid isprevented from leaking more securely.

In the present invention, when a check valve is attached in the feedingbottle, such a mechanism is not required in the artificial nipple sothat the structure of the artificial nipple is simplified, andproduction, replacement, cleaning, or the like can be executed moreeasily. However, a check valve attached to the artificial nipple willnot cause any problem in implementation of the present invention. Inthis case, there is no need to provide a check valve in the feedingbottle, however, the embodiment in which the check valve is provided inthe feeding bottle is more preferably from the view point of productionaspect and production cost of the artificial nipple regarding theproblem of D.

Regarding the point B, in order to prevent air from accumulating in astomach or intestines, fitting of the nipple to the mouth of a infant orthe like is important. It is known that when an artificial nipple isused, an infant creates a negative pressure with its tongue and hardpalate and swallows the liquid feed. However, in rodents, for example,when an infant becomes 10 days old, cutting teeth grow significantly andair is swallowed together because of the extended cutting teeth thatform obstacles. For addressing this problem, the nipple is made largerin accordance with the growth of the infant so that the cutting teethwill not be obstacles, thereby making it easy to produce a negativepressure with the tongue and the hard palate (lips) as if a human sucksliquid with a straw, and preventing the air from entering. In the caseof experimental animals other than rodents (for example, ferret), therearises a case that not only the size of the nipple but also the shape ofthe nipple should be changed in accordance with the shape of the mouthof that animal. Also in such a case, it is important to adopt astructure that prevents liquid from accumulating in the nipple, and bythe help of this structure, it is possible to flexibly correspond to thechange in shape of the nipple.

Regarding the point C, intake amount of the liquid feed or the like wascomprehended by attaching a tube with calibrations into the feedingbottle. In addition to the calibrations, the tube has a movable mark.This movable mark can be used for comprehension of an intake amount byshifting the mark in accordance with the liquid level line when theliquid feed is continuously fed to a plurality of infants, or forindication of the maximum liquid level line when the liquid is injectedinto the feeding bottle. Further, for enabling selection of the tubediameter according to the size of the experimental animal, the tubeitself is made replaceable. In addition to these structures, a spacerfor replacement of tube is prepared separately.

Regarding the point D, as described in A, the structure that preventsliquid from accumulating in the nipple except in the nipple tip and theduct realized by filling the nipple with an elastic member or integrallyforming the nipple with an elastic member is not only effective insimplification of the structure of the artificial nipple but alsoeffective in preventing liquid from leaking when an experimental animalbites the nipple.

Through the above solving means, the inventors of the presentapplication made it possible to establish and provide an artificialnipple favorably used in giving a liquid feed or the like to infants ofexperimental animals, in particular, mice and rats, voluntarily andorally, and a feeding bottle designed to use the artificial nipple in afavorable manner, a liquid feeding method for experimental animalscomprising the artificial nipple and the feeding bottle, and a methodthereof.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, preferred embodiments of the present invention will bedescribed in more detail with reference to FIGS. 1, 2, 3, and 4.

FIG. 1 shows an artificial nipple of the present invention. In thisdrawing, the numeral 01 is an essential part of the artificial nippleincluding a silicone rubber outer wall, and a nipple and a nipple tipintegrally formed with silicone sponge or its elastic member, and thenumerals 02 and 02′ represent a junction with a feeding bottle.

In the nipple tip 03, a notch indicated by 06 or a hole indicated by 06′is provided so as to feed a liquid in response to the sucking action ofthe animal. In the case of the notch 06, the strength of the suckingaction by the animal gives a similar effect to changing the borediameter, so that it is more suitably used in the artificial nipple ofthe present invention.

The inner diameter of the duct indicated by 07 to be attached mayappropriately be changed in consideration of the objective experimentalanimal, its age, viscosity of the liquid feed and the like. The innerdiameter may be, for example, 25G to 27G in gauge of injection needle,and this can control the degree of outflow of the liquid feed or thelike. The length of the duct is for example 10 mm to 14 mm, although itdiffers depending on the size of the nipple.

The duct can be formed of any material that can keep the inner diameter,and such material may be appropriately selected from the hard tubularmembers used in solution sending purpose. A stainless tube commonly usedas an injection needle is preferably used.

Since the diameter of the duct can be changed, the present invention canbe appropriately applied to a variety of liquid feed or the likeincluding those having low viscosity such as water, various aqueoussolutions, and transfusion compositions, as well as those having highviscosity such as milk for experimental animals and enteral nutrients.

When a silicone outer wall is used in the nipple 05, the outer wall isabout 0.1 to 0.4 mm thick. The inside of the outer wall is filled withan elastic member such as silicone sponge except in the nipple tip as isdenoted by 04. By filling the nipple except in the nipple tip and theduct with the elastic member, a structure that prevents accumulation ofliquid is realized. This is a solution for the problem that when anexperimental animal bites the nipple in which a liquid feed or the likeaccumulates, the nipple is crushed and a large amount of liquid rushesout at once. The structure that prevents accumulation of liquid canadvantageously prevent the liquid from leaking. The elastic member usedherein may be of any materials lacking hygroscopicity and applicable tofood containers or the like, and members formed of materials other thansilicone and polymeric rubbers can also be used if they can giveelasticity when made into a sponge-like structure.

When the artificial nipple is designed for repeated use, the outer walland the filler are preferably made of materials that are resistive toheat sterilization. As such materials, isoprene, silicone,styrene-butadiene copolymer and the like rubbers, and sponges derivedtherefrom can be chosen. Among these, silicone foam is preferably usedas a filler because its elasticity can be appropriately adjusted in asimple manner. When the artificial nipple is not used repeatedly, latexrubber is also excellent as a material for the nipple from the viewpoint of ease of sucking by experimental animals.

In order to prevent the liquid feed or the like from counterflowing, itis necessary to place a check valve. When the check valve is attached tothe artificial nipple, it is placed together with a base 12 of, e.g.,silicone rubber in the junction with the feeding bottle as indicated by11 in FIG. 1. The check valve may be formed of materials having similarelasticity or moderate hardness compared to the elastic member used inthe nipple, including elastomers such as silicone and polypropylene orhybrids thereof.

The numeral 08 denotes a supporting part of the duct formed of siliconerubber or the like, and is adapted to the diameter of the duct 07. Thenumeral 09 denotes a flange-shaped base part of the nipple which fixesthe artificial nipple when joined to the feeding bottle. The numeral 10denotes an allowance provided so as to follow the variable diameter ofthe duct 07.

Four artificial nipples designed for each of mouse and rat shown in FIG.4 are formed into four different sizes, i.e., small, regular, large, andextra large, respectively and they can be appropriately selecteddepending on the age and size of the experimental animal. By attachingan artificial nipple which is suited to the size of mouth of theexperimental animal to the feeding bottle in any time, it is possible toprevent air from being sucked during the feeding. The values indicatedin FIG. 4 are given just for reference, and are not limitative.

As described above, according to the present invention, it is possibleto prepare an artificial nipple which is fitted to the mouth shape ofthe animal depending on the size and situation of the animal. This isone of the features of the present invention. Therefore, the presentinvention is applicable to a variety of experimental animals includingrelatively large experimental animals such as rabbit and experimentalanimals having a different mouth shape from that of the rodent such asferret, as well as mouse, guinea pig, and rat.

In one embodiment, the feeding bottle of the present invention has acheck value 14 in FIG. 2. When the feeding bottle is combined with theartificial nipple not having a check valve shown in FIG. 1, moreexcellent feature is realized by the article of the present invention.To be more specific, the structure of the artificial nipple issimplified, and production of the artificial nipple is facilitated. Inassociation with this, nipples of different sizes can be readilyprepared, and the feeding condition can be changed so as to be suitedfor various purposes only by changing the artificial nipple that issuited for the condition, which is more suitable for the object of thepresent invention. Also an advantage is provided that recycling bycleaning of the artificial nipple is facilitated. However, when the sizeof the artificial nipple is relatively large, or when no significantproblem arises in production or handling thereof, the constitutionproviding a check value in the artificial nipple as indicated by 11 inFIG. 1 does not cause any problem in implementation of the presentinvention.

The article of the present invention has the following excellent featureby having a replaceable tubular structure in the feeding bottle asindicted by 16 in FIG. 2.

In brief, since the tube is replaceable, even when the size of theanimal is changed from mouse to rat, the same feeding bottle can be usedboth for rat and mouse by changing the tube via a spacer 21. Bypreparing spacers of different diameter, tubes of different diameterscan be joined to only one feeding bottle having an outer wall 19.

When the tube has calibrations, the amount of the liquid feed that isactually given or administered to the experimental animal can be readilymeasured for individual animals. In this case, in addition to thecalibration written to the tube as indicated by 16 in FIG. 2, a movablemark formed of silicone rubber or various resins may be attached. Bymoving the movable mark in accordance with the feeding amount for eachinfant, it is possible to measure the intake amount of the liquid feedmore accurately. This movable mark can be formed into a ring, forexample, and a required number of movable marks can be fit around thetube.

Any materials having such transparency that allows checking of thecontent and having such hardness that allows measurement can be used forthe tube, and for example, glass, polypropylene, polycarbonate,methylpentene resin, or silicone rubber that is commonly used for a tubefor injection can be used.

By making the diameter “d” at the joint between the tube and the feedingbottle in the tube coincide with the diameter of an insertion port ofthe feeding bottle, it is possible to facilitate replacement of thetube. In this case, the spacer 21 is not necessary. The “d” is set fromthe view point of check of the liquid level and in accordance with theintake amount of the feed of the animal. For example, in the case of amouse, a tube having “d” of about 3 mm may be used.

An artificial nipple joint base 15 and a duct supporter 20 shown in FIG.2 are formed of rubber or the like and have detachable structures.Therefore, not only cleaning and repair of the feeding bottle, but alsochanging of size and material of each part depending on the experimentalanimal can be readily conducted.

The numeral 18 denotes a tube used for air vent and cleaning of feedingbottle, and the numeral 17 indicates a tube through which a liquid feedor the like is introduced. These tubes can be formed of similarmaterials as described above for the tube. The numeral 22 denotes a tubefor junction which facilitates detachment of the tube or the like, andis implemented by a stainless tube or the like.

The length of each part of the feeding bottle shown by 13 in FIG. 2 canbe appropriately changed depending on the use method and purpose. Forexample, the length L in FIG. 2 is about 100 mm in the case of a mouseinfant, however, it may be selected longer when the ability of drinkingmilk of the animal is higher.

As one embodiment, the feeding bottle of the present invention has afine adjustment mechanism of flow rate as shown in FIG. 3. The fineadjustment mechanism of flow rate is implemented by attaching to thefeeding bottle of FIG. 2, a liquid volume adjusting tube having acapacity smaller by 20-30% than an expected amount of liquid which aninfant will drink at one time and a pressurizing tube and making theinterior of the feeding bottle a closed system. The internal pressurewas adjusted with these two tubes, whereby supply of liquid inaccordance with the suction-drinking amount by the infant, prevention ofleak of the liquid and urging to start suction-drinking aresimultaneously realized.

In brief, when milk or the like is fed and the infant takes theartificial nipple in its mouth, a slight pressure is applied on thepressurizing tube with hands or fingers for giving milk or the like tocause a small amount of the milk or the like to flow out of the nippletip of the artificial nipple. This urges the suctioning and drinkingaction of the infant and the infant rapidly starts suction-drinking.With this mechanism, it is possible to significantly reduce the waitingtime until the infants voluntarily starts suction-drinking. As theinfant sucks and drinks, the internal pressure of the feeding bottlebecomes negative, and the liquid volume adjusting tube turns into the acondition B from a condition A shown in FIG. 3 to stop feeding of themilk or the like. At this point, if further suction-drinking action ofthe infant is observed, the pressurizing tube is pressed with hands orfingers to make the liquid volume adjusting tube into a condition C,thereby allowing suction-drinking again. As the infant suction-drinksagain, the liquid volume adjusting tube turns to the condition B againto stop feeding of the liquid. With this mechanism, it is possible tocorrespond to differences in suck-drinking amount of individual infantmore finely, and to prevent the liquid from leaking more securely. Whenanother infant is fed subsequently, the feeding bottle is made into anopen system, and then the liquid adjusting tube is returned to thecondition A.

In order to realize the above configuration, the liquid volume adjustingtube has such a thickness that the tube will be crushed with noresistance for avoiding influence on suction-drinking of the infant.When the material is silicone rubber, the thickness is approximately0.05 mm, for example, and this thickness is the minimum for maintainingthe shape. The pressurizing tube and the connecting tube may have suchthicknesses that the tubes will not be crushed at a negative pressuregenerated when an infant drinks milk or the like. When the material issilicone rubber, the thickness is about 0.5 mm, for example.

The materials for the pressurizing and connecting tubes may be anymaterials insofar as they can realize the aforementioned functions andare resistant to heat sterilization, and isoprene rubber, polypropylenerubber and the like can be exemplified. However, it is to be noted thatthe required thickness differs depending on the material. These tubescan be joined via a stainless tube or the like which isheat-sterilizable in consideration of replacement or the like of thetubes. Likewise the case of the tube with calibrations, by using aspacer, it is possible to readily replace tubes of different diameters.

A liquid feeding device for experimental animals having the excellentfeatures as described above, enabling voluntary and oral feeding of aliquid feed or the like to an experimental animal such as mouse or ratin a suckling period which corresponds to an immature baby of humanbeing, and enabling regular and quantitative feeding of a liquid withbeing held by a hand is not known up to now, and is first realized bythe present invention. The artificial nipple, the feeding bottle suitedfor use in combination with the artificial nipple, a liquid feedingdevice for experimental animals comprising the artificial nipple and thefeeding bottle, and a liquid feeding method for experimental animals inwhich the artificial nipple in the device is changed in accordance withthe condition of the experimental animal have many excellent features.

Efficacy of the present invention will be explained based on the testexamples, however, the present invention is not limited to these testexamples.

TEST EXAMPLE 1

Artificial suckling of mouse using an artificial nipple and a feedingbottle for mouse; realization of growth by voluntary suckling of infant

Test method: With respect to home-bred and naturally born BALB/C mice atone day old, artificial suckling using a nipple of small size for mouseand a feeding bottle of the present invention was started. A nursingcage for artificial suckling was kept warm on a commercially availablehot carpet. In the warm cage laid with chips a bamboo bag was placed,and a mouse infant was accommodated therein. Chips outside the bamboobag were occasionally poured with water so that moisture was alwayskept. Before starting the artificial suckling, mice were separated fromtheir parent for 3 to 4 hours. Artificial milk was prepared bydissolving 3.8 g of dog milk in 10 mL of warm water. After introducingthe milk into the feeding bottle equipped with the artificial nipple bymeans of a pump, heat was applied for about 3 to 5 minutes while thefeeding bottle was inserted into a copper tube that is warmed underreflux by warm water. Heat application was conducted every time oroptionally as necessary before suckling each infant. Milk was fed fiveor six times, or four or five times at 10 days old or later in the termbetween 8:00 a.m. and 10:00 p.m. The intake amount of the milk wasdetermined by measuring a reduced amount of milk in the tube (length oftube: cm) in the feeding bottle between before and after suckling, andmeasuring body weight of infant before and after the suckling. Inartificially suckled infants, sucking was not allowed from 10:00 p.m. to8:00 a.m. next morning. The artificially suckled infants were kept ingroup, and were not returned to breast feeding. Micturition and bowelmovement were urged by gently press the upper abdomen and back of thebladder several times per day as was necessary. Infants ofbreast-feeding group were fed together with the mother animal in usualconditions in a normal cage.

Results of Experiments: The Results are Shown in FIG. 5

Although the artificially suckled infants were inferior in growth rateto the breast-fed infants, they continuously took the artificial milkvoluntarily at the time of feeding and all of them grew without anydropout.

TEST EXAMPLE 2

A certain amount of test solution was orally administered using thearticle of the present invention in place of a gastric probe, and theinfluence on the growth of mouse infant exerted by the administration oftest solution by the present invention was examined.

Test method: 3 BALB/C mice at 12 days of pregnancy purchased from JAPANSLC were allowed to naturally bear in a stainless cage with a clean cap.In 24 hours after bearing, infants were divided into two groups for eachparent, and combined so that each group equally contains infants fromrespective parents. Two parents each were made to feed a total of 8infants. The test solution used in this experiment was as follows. 0.5%fructooligosaccharide-0.2 M-sucrose aqueous solution was uses as a testsolution. The test solution was introduced into the feeding bottle formouse of the present invention using a disposable injector with asterilized tapered tip, and kept warm for 4 minutes in an incubator at50° C. The mouse infants were separated from the parent at 1 day and 2days, and kept warm for 2 hours in a plastic cage floating in a waterbath at 43° C. When a mouse infant drank 0.7 mm by calibrations on thefeeding bottle for mouse (about 50 μL) of test solution from anartificial nipple of small size for mouse of the present invention, thenipple was immediately removed from the mouth. Then the same amount of0.2M-sucrose aqueous solution was made to drink. This allowed accuratedetermination of the drinking amount of the test solution. The controlgroup was made to drink 0.2M-sucrose aqueous solution in the samemanner. After administration of the test solution, the mouse infantswere immediately returned to the cage of its mother (feeding mother).

Results of experiment: Growth curves of infants are shown in FIG. 6. Themouse infants orally administered with the test solution using thearticle of the present invention normally grew.

It was confirmed that in experimental systems for examining influencesof orally administered drugs or the like, the article of the presentinvention can be effectively used even for the experimental animals suchas mouse or rat infants for which use of a gastric probe and a catheteris difficult.

INDUSTRIAL APPLICABILITY

As is apparent from the results of the test examples and the like, bythe artificial nipple, the feeding bottle suited for use with theartificial nipple, the liquid feeding device for experimental animalscomprising the artificial nipple and the feeding bottle, and the liquidfeeding method for experimental animals in which the artificial nipplein the above device is replaced in accordance with the condition of theexperimental animal, voluntary intake of liquid feed or the like byexperimental animals is enabled, and artificial suckling of mouse infantor the like corresponding to a human immature baby whose eyes and earsare not open is enabled. Such artificial suckling was almost impossibleup to now. Further, since the present invention made it possible toadminister a variety of test solutions to mouse or rat infantsvoluntarily and orally, it is possible to evaluate the effect of orallyadministered various test solutions in a natural manner for animals insuckling period which have not been realized regardless of their highsensitivity to drugs and usability as experimental systems. This made itpossible to develop new drugs and foods for immature babies and forinfants that have not been developed yet.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of an artificial nipple of the presentinvention.

FIG. 2 is a partial cross-sectional view of a feeding bottle of thepresent invention.

FIG. 3 is a cross-sectional view showing a mechanism for controlling theinternal pressure of the feeding bottle.

FIG. 4 is a view showing an example in which the artificial nipple ischanged depending on the size of the experimental animal.

FIG. 5 is a view showing results of the test example in which mouseinfants are artificially suckled using an article of the presentinvention.

FIG. 6 is a view showing results of the test example in which mouseinfants are orally and voluntarily administered with a test solution.

1. An artificial nipple for an experimental animal comprising: areplaceable duct in a nipple; and a structure that prevents a liquidfrom accumulating in the nipple except in a nipple tip and the duct. 2.The artificial nipple for an experimental animal according to claim 1,wherein the structure that prevents the liquid from accumulating isachieved by filling the nipple with an elastic member or forming thenipple with an elastic member integrally with an outer wall of thenipple.
 3. The artificial nipple for an experimental animal according toclaim 1, wherein a check valve is provided in a joint part with afeeding bottle.
 4. A feeding bottle for an experimental animal used incombination with the artificial nipple of claim 1, the feeding bottlecomprising therein a replaceable tube.
 5. The feeding bottle for anexperimental animal according to claim 4, wherein the tube is markedwith calibrations for measurement and/or a movable mark.
 6. The feedingbottle for an experimental animal according to claim 4, comprising acheck valve.
 7. The feeding bottle for an experimental animal accordingto claim 4, comprising a mechanism by which a liquid stops flowing whenan experimental animal drinks a predetermined amount or a certain amountof the liquid and thereby the internal pressure of the feeding bottlebecomes negative.
 8. The feeding bottle for an experimental animalaccording to claim 7, comprising a mechanism by which the experimentalanimal is allowed to voluntarily drink the liquid again upon applicationof a pressure from outside the feeding bottle after the liquid stopsflowing when the experimental animal drinks the predetermined amount orthe certain amount of the liquid and thereby the internal pressure ofthe feeding bottle becomes negative.
 9. A liquid feeding device for anexperimental animal, wherein the artificial nipple according to claim 1is attached to a feeding bottle including therein a replaceable tube,wherein the tube is marked with calibrations for measurement and/or amovable mark.
 10. A feeding bottle for an experimental animal used incombination with the artificial nipple of claim 2, the feeding bottlecomprising therein a replaceable tube.
 11. The feeding bottle for anexperimental animal according to claim 10, wherein the tube is markedwith calibrations for measurement and/or a movable mark.
 12. The feedingbottle for an experimental animal according to claim 10, comprising acheck valve.
 13. The feeding bottle for an experimental animal accordingto claim 11, comprising a check valve.
 14. The feeding bottle for anexperimental animal according to claim 5, comprising a check valve. 15.The feeding bottle for an experimental animal according to claim 10,comprising a mechanism by which a liquid stops flowing when anexperimental animal drinks a predetermined amount or a certain amount ofthe liquid and thereby the internal pressure of the feeding bottlebecomes negative.
 16. The feeding bottle for an experimental animalaccording to claim 11, comprising a mechanism by which a liquid stopsflowing when an experimental animal drinks a predetermined amount or acertain amount of the liquid and thereby the internal pressure of thefeeding bottle becomes negative.
 17. The feeding bottle for anexperimental animal according to claim 12, comprising a mechanism bywhich a liquid stops flowing when an experimental animal drinks apredetermined amount or a certain amount of the liquid and thereby theinternal pressure of the feeding bottle becomes negative.
 18. Thefeeding bottle for an experimental animal according to claim 13,comprising a mechanism by which a liquid stops flowing when anexperimental animal drinks a predetermined amount or a certain amount ofthe liquid and thereby the internal pressure of the feeding bottlebecomes negative.
 19. The feeding bottle for an experimental animalaccording to claim 18, comprising a mechanism by which the experimentalanimal is allowed to voluntarily drink the liquid again upon applicationof a pressure from outside the feeding bottle after the liquid stopsflowing when the experimental animal drinks the predetermined amount orthe certain amount of the liquid and thereby the internal pressure ofthe feeding bottle becomes negative.
 20. A liquid feeding device for anexperimental animal, wherein the artificial nipple according to claim 2is attached to a feeding bottle that includes therein a replaceabletube, and the tube is marked with calibrations for measurement and/or amovable mark, and the feeding bottle includes a check valve.